WO2020063988A1 - Polythérapie combinant anticorps anti-cldn18 et médicaments chimiothérapeutiques - Google Patents

Polythérapie combinant anticorps anti-cldn18 et médicaments chimiothérapeutiques Download PDF

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WO2020063988A1
WO2020063988A1 PCT/CN2019/109214 CN2019109214W WO2020063988A1 WO 2020063988 A1 WO2020063988 A1 WO 2020063988A1 CN 2019109214 W CN2019109214 W CN 2019109214W WO 2020063988 A1 WO2020063988 A1 WO 2020063988A1
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amino acid
acid sequence
variable region
chain variable
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PCT/CN2019/109214
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李宗海
王华茂
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科济生物医药（上海）有限公司
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Priority to CN201980065066.XA priority Critical patent/CN112888458A/zh
Priority to US17/281,372 priority patent/US20220033491A1/en
Priority to JP2021517792A priority patent/JP2022511394A/ja
Priority to KR1020217013109A priority patent/KR20210072027A/ko
Priority to EP19866728.9A priority patent/EP3858384A4/fr
Publication of WO2020063988A1 publication Critical patent/WO2020063988A1/fr

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    • A—HUMAN NECESSITIES
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the invention belongs to the field of biomedicine, and particularly relates to a combination therapy of CLDN18 antibody and chemotherapeutic drug.
  • Gastric cancer is one of the cancers with a high incidence worldwide. According to statistics from the World Health Organization's Cancer Control Project, as many as 7 million patients die from cancer each year worldwide, of which 700,000 die from gastric cancer.
  • German biotechnology company Ganymed reported the combination of chemotherapy drugs with EOX (epirubicin, oxaliplatin, and capecitabine) and antibodies targeting Claudin 18.2 for gastric cancer
  • EOX epirubicin, oxaliplatin, and capecitabine
  • EP2852408B also reported the use of EOF (epirubicin
  • chemotherapeutic drugs Staurexin
  • CLDN cell junction clin
  • chemotherapeutic drugs usually have large cytotoxicity, and the patients are poorly tolerated, the use of multiple chemotherapeutic drugs brings a great risk of clinical application.
  • the object of the present invention is to provide a combination therapy of antibodies and chemotherapeutic drugs for CLDN18, which is used to effectively treat diseases related to the expression of CLD18A.
  • a method for treating a CLDN18-positive tumor administering to an individual in need thereof an antibody that specifically recognizes CLDN18, 5-fluorouracil or a prodrug thereof or an active metabolite thereof, and oxaliplatin Or a prodrug or an active metabolite thereof; or an antibody in need of specific recognition of CLDN18, 5-fluorouracil or a prodrug thereof or an active metabolite thereof, oxaliplatin or a prodrug thereof or an active metabolite thereof, And a taxane drugs.
  • an individual in need thereof is given an antibody that specifically recognizes CLDN18, 5-fluorouracil or a prodrug thereof, and oxaliplatin or a prodrug thereof is given to an individual in need, an antibody that specifically recognizes CLDN18, 5 -Fluorouracil or a prodrug thereof, oxaliplatin or a prodrug thereof, and a taxane drug.
  • the prodrug of 5-fluorouracil is capecitabine.
  • the CLDN18 is CLDN18.2.
  • the antibody specifically recognizes CLDN18.2 and does not recognize CLDN18.1.
  • the antibodies of CLDN18, 5-fluorouracil or a prodrug thereof or an active metabolite thereof, oxaliplatin or a prodrug thereof or an active metabolite thereof are administered in any order.
  • antibodies to 5-fluorouracil or its prodrug or its active metabolite, oxaliplatin, CLDN18 are administered on the same day.
  • the CLDN18 antibody is administered at a dose of 500-1200 mg / m 2 / time. In a preferred example, it is 500-1000 mg / m 2 / time. In a preferred example, it is 500-900 mg / m 2 / time. In a preferred example, it is 600-800 mg / m 2 / time.
  • the CLDN18 antibody is administered at a dose of 20-300 mg / kg / time. In a preferred example, it is 20 to 100 mg / kg / time. In a preferred example, it is 20-50 mg / kg / time.
  • the 5-fluorouracil or its prodrug or its active metabolite is administered at a dose of 300-900 mg / m 2 / time.
  • 5-fluorouracil is administered in an amount of 300-800 mg / m 2 / time.
  • capecitabine is administered at 600-700 mg / m 2 / time. In a preferred example, it is 625 mg / m 2 / time.
  • the 5-fluorouracil or its prodrug or its active metabolite is administered at a dose of 50 to 70 mg / kg / time.
  • 5-fluorouracil is administered in an amount of 50 to 70 mg / kg / time.
  • the application amount of 5-fluorouracil is 50 to 60 mg / kg / time.
  • the oxaliplatin or its prodrug or its active metabolite is administered at a dose of 50-300 mg / m 2 / time. In a preferred example, oxaliplatin is administered at 100 to 200 mg / m 2 / time. In a more preferred example, oxaliplatin is administered at 130 mg / m 2 / times.
  • the oxaliplatin or its prodrug or its active metabolite is administered at a dose of 1 to 10 mg / kg / time. In a preferred example, oxaliplatin is administered at 1 to 5 mg / kg / time.
  • the antibody that specifically recognizes CLDN18 is a humanized antibody or a chimeric antibody.
  • the antibody that specifically recognizes CLDN18 comprises:
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 16 HCDR2 shown in the amino acid sequence of NO: 17, 40, or 41
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 34 HCDR2 shown in the amino acid sequence of SEQ ID NO: 35 or 42
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 36 and amino acid sequence of SEQ ID NO: 37
  • LCDR2 shown in the amino acid sequence of SEQ ID NO: 39
  • amino acid sequence of SEQ ID NO: 39 or
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 25 LCDR1, LCDR2 shown in the amino acid sequence of SEQ ID NO: 26, and LCDR3 shown in the amino acid sequence of SEQ ID NO: 27; or,
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 28 HCDR2 shown in the amino acid sequence of SEQ ID NO: 29, HCDR3 shown in the amino acid sequence of SEQ ID NO: 30, and HCDR3 shown in the amino acid sequence of SEQ ID NO: 31 LCDR1, LCDR2 shown in the amino acid sequence of SEQ ID NO: 32, and LCDR3 shown in the amino acid sequence of SEQ ID NO: 33; or,
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 43 HCDR2 shown in the amino acid sequence of SEQ ID NO: 44
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 46 LCDR1, LCDR2 shown in the amino acid sequence of SEQ ID NO: 47
  • LCDR3 shown in the amino acid sequence of SEQ ID NO: 48 or,
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 49 HCDR2 shown in the amino acid sequence of SEQ ID NO: 50
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 51 and amino acid sequence of SEQ ID NO: 52
  • LCDR3 shown in the amino acid sequence of SEQ ID NO: 54 LCDR1, LCDR3 shown in the amino acid sequence of SEQ ID NO: 53
  • LCDR3 shown in the amino acid sequence of SEQ ID NO: 54 LCDR1, LCDR3 shown in the amino acid sequence of SEQ ID NO: 53
  • the antibody that specifically recognizes CLDN18 comprises:
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 34 HCDR2 shown in the amino acid sequence of SEQ ID NO: 35 or 42
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 36 and amino acid sequence of SEQ ID NO: 37
  • LCDR2 shown in the amino acid sequence of SEQ ID NO: 39
  • amino acid sequence of SEQ ID NO: 39 or
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 43
  • HCDR2 shown in the amino acid sequence of SEQ ID NO: 44
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 45
  • amino acid sequence of SEQ ID NO: 46 The LCDR1 shown in the amino acid sequence of SEQ ID NO: 47 and the LCDR3 shown in the amino acid sequence of SEQ ID NO: 48.
  • the antibody that specifically recognizes CLDN18 contains:
  • the antibody that specifically recognizes CLDN18 contains:
  • the antibody that specifically recognizes CLDN18 contains:
  • the antibody that specifically recognizes CLDN18 is selected from:
  • the CLDN18-positive tumors include: gastric cancer, pancreatic cancer, esophageal cancer, and lung cancer.
  • the taxane drug is selected from paclitaxel, albumin-bound paclitaxel, and docetaxel; preferably, it is albumin-bound paclitaxel.
  • kits combination for treating CLDN18-positive tumors.
  • the kit combination includes a kit A and a kit B.
  • the kit A includes an antibody that specifically recognizes CLDN18.
  • the kit B includes a chemotherapeutic drug, the chemotherapeutic drug is: 5-fluorouracil or a prodrug thereof or an active metabolite thereof, oxaliplatin or a prodrug thereof or an active metabolite thereof; or, 5-fluorouracil or a prodrug thereof Or its active metabolite, oxaliplatin or its prodrug or its active metabolite, and a taxane drug.
  • the kit A and the kit B are administered to an individual in need, wherein the kit B includes 5-fluorouracil or a prodrug thereof, and oxaliplatin or a prodrug thereof; or to an individual in need thereof Kit A and Kit B, wherein Kit B includes 5-fluorouracil or a prodrug thereof, oxaliplatin or a prodrug thereof, and a taxane drug.
  • the prodrug of 5-fluorouracil is capecitabine.
  • the CLDN18 is CLDN18.2.
  • the antibody specifically recognizes CLDN18.2 and does not recognize CLDN18.1.
  • kit A and kit B are administered in no particular order.
  • 5-fluorouracil or its prodrug or its active metabolite, oxaliplatin-containing kit B, and CLDN18-containing antibody kit A are administered on the same day.
  • the CLDN18 antibody is administered at a dose of 500 to 1200 mg / m 2 / time. In a preferred example, it is 500-1000 mg / m 2 / time. In a preferred example, it is 500-900 mg / m 2 / time. In a preferred example, it is 600-800 mg / m 2 / time.
  • the CLDN18 antibody is administered at a dose of 20 to 300 mg / kg / time. In a preferred example, it is 20 to 100 mg / kg / time. In a preferred example, it is 20-50 mg / kg / time.
  • the 5-fluorouracil or prodrug or active metabolite thereof is administered at a dose of 300 to 900 mg / m 2 / time.
  • 5-fluorouracil is administered in an amount of 300-800 mg / m 2 / time.
  • capecitabine is administered at 600-700 mg / m 2 / time. In a preferred example, it is 625 mg / m 2 / time.
  • the 5-fluorouracil or prodrug or active metabolite thereof is administered at a dose of 50 to 70 mg / kg / time.
  • 5-fluorouracil is administered in an amount of 50 to 70 mg / kg / time.
  • the application amount of 5-fluorouracil is 50 to 60 mg / kg / time.
  • the oxaliplatin or its prodrug or its active metabolite is administered at a dose of 50 to 300 mg / m 2 / time. In a preferred example, oxaliplatin is administered at 100 to 200 mg / m 2 / time. In a more preferred example, oxaliplatin is administered at 130 mg / m 2 / times.
  • the oxaliplatin or its prodrug or its active metabolite is administered at a dose of 1 to 10 mg / kg / time. In a preferred example, oxaliplatin is administered at 1 to 5 mg / kg / time.
  • the antibody that specifically recognizes CLDN18 is a humanized antibody or a chimeric antibody.
  • the antibody that specifically recognizes CLDN18 comprises:
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 34 HCDR2 shown in the amino acid sequence of SEQ ID NO: 35 or 42
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 36 and amino acid sequence of SEQ ID NO: 37
  • LCDR2 shown in the amino acid sequence of SEQ ID NO: 39
  • amino acid sequence of SEQ ID NO: 39 or
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 25 LCDR1, LCDR2 shown in the amino acid sequence of SEQ ID NO: 26
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 28 HCDR2 shown in the amino acid sequence of SEQ ID NO: 29, HCDR3 shown in the amino acid sequence of SEQ ID NO: 30, and HCDR3 shown in the amino acid sequence of SEQ ID NO: 31 LCDR1, LCDR2 shown in the amino acid sequence of SEQ ID NO: 32, and LCDR3 shown in the amino acid sequence of SEQ ID NO: 33; or
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 43 HCDR2 shown in the amino acid sequence of SEQ ID NO: 44
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 46 LCDR1, LCDR2 shown in the amino acid sequence of SEQ ID NO: 47
  • LCDR3 shown in the amino acid sequence of SEQ ID NO: 48 or
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 49 HCDR2 shown in the amino acid sequence of SEQ ID NO: 50
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 51 and amino acid sequence of SEQ ID NO: 52
  • LCDR3 shown in the amino acid sequence of SEQ ID NO: 54 LCDR1, LCDR3 shown in the amino acid sequence of SEQ ID NO: 53
  • LCDR3 shown in the amino acid sequence of SEQ ID NO: 54 LCDR1, LCDR3 shown in the amino acid sequence of SEQ ID NO: 53
  • the antibody that specifically recognizes CLDN18 includes:
  • HCDR1 shown in the amino acid sequence of SEQ ID NO: 34 HCDR2 shown in the amino acid sequence of SEQ ID NO: 35 or 42
  • HCDR3 shown in the amino acid sequence of SEQ ID NO: 36 and amino acid sequence of SEQ ID NO: 37
  • LCDR2 shown in the amino acid sequence of SEQ ID NO: 39.
  • the antibody that specifically recognizes CLDN18 contains:
  • the antibody that specifically recognizes CLDN18 contains:
  • the antibody that specifically recognizes CLDN18 contains:
  • the antibody that specifically recognizes CLDN18 is selected from:
  • the CLDN18-positive tumors include: gastric cancer, pancreatic cancer, esophageal cancer, and lung cancer.
  • the taxane drug is selected from paclitaxel, albumin-bound paclitaxel, and docetaxel; preferably, it is albumin-bound paclitaxel.
  • a pharmaceutical composition for treating CLDN18-positive tumors wherein the pharmaceutical composition includes an antibody that specifically recognizes CLDN18 and a chemotherapeutic drug, and the chemotherapeutic drug is as described above 5-fluorouracil or its prodrug or its active metabolite, oxaliplatin or its prodrug or its active metabolite; or 5-fluorouracil or its prodrug or its active metabolite, oxaliplatin or its prodrug Drugs or their active metabolites, and a taxane drugs; the antibody that specifically recognizes CLDN18 is an antibody as described above.
  • kits combination or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating a CLDN18-positive tumor.
  • the above-mentioned kit combination or pharmaceutical composition is provided for treating CLDN18-positive tumors.
  • FIG. 1 is a tumor volume statistical chart of a BALB / c nude mouse bearing a human gastric cancer PDX-GA0006 model after being treated with different treatment schemes;
  • FIG. 2 is a statistical chart of body weight of BALB / c nude mice bearing human gastric cancer PDX-GA0006 model after being treated with different treatment schemes;
  • FIG. 3 is a tumor photograph of a BALB / c nude mouse bearing a human gastric cancer PDX-GA0006 model after being treated with different treatment schemes;
  • FIG. 4 is a statistical graph of tumor weights of BALB / c nude mice bearing human gastric cancer PDX-GA0006 model after being treated with different treatment schemes. Note: Compared with the solvent group, * indicates P ⁇ 0.05, ** indicates P ⁇ 0.01, and *** indicates P ⁇ 0.001;
  • FIG. 5 shows the effect of different doses of antibodies on antitumor effects
  • Figure 6 shows the effect of different doses of antibodies on mouse body weight.
  • the present inventors After intensive research and repeated experiments, the present inventors have obtained a method for treating tumors by combining antibodies targeting CLDN18.2, 5-fluoropyrimidine, and oxaliplatin.
  • the tumors are tumors that express the dense protein 18A2, especially gastric cancer. , Pancreatic cancer, esophageal cancer, lung cancer treatment.
  • the antibody of the present invention is an antibody that specifically binds to an epitope present on cladin 18A2 (CLDN18A2), and includes a polyclonal antibody and a monoclonal antibody, preferably a monoclonal antibody.
  • Monoclonal antibodies encompassed by the invention include IgA, IgG1-4, IgE, IgM, and IgD antibodies. In one embodiment, the antibody is an IgG1 antibody.
  • the antibody may also be an IgG3 antibody, such as an IgG3 ⁇ or IgG3 ⁇ isotype; it may also be an IgG4 antibody, such as an IgG4 ⁇ or IgG4 ⁇ isotype; or it may be IgA1 or IgA2
  • the antibody may be an IgM antibody.
  • the CLD18A2 antibody is administered at a dose of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 / kg / time; 1, 2, 3, per week 4, 5, 6, or 7 times; injections for 1 week, or continuous injections for 2, 3, 4, 5, or 6 weeks.
  • the CLD18A2 antibody is administered at a dose of 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1050, 1100, 1150, 1200 mg / m 2 / times; 1, 2, 3, 4, 5 or 6 times per week; 1 week injection, or 2, 3, 4, 5 or 6 consecutive injections week.
  • CLDN18.2 includes isoforms, mammalian (e.g., human) CLDN18.2, posttranslationally modified variants of human CLDN18.2, isoforms and interspecies homologs, and includes at least one Of the common epitope.
  • the amino acid sequence of CLDN18.2 e.g., human CLDN18.2
  • CLDN18A2 is known in the art, as shown in the NCBI database.
  • CLDN18.2 and “cell-linkin 18.2” are used interchangeably herein, and the terms “CLDN18A1", “CLDN18.1”, and “cell-linkin 18.1” are interchangeable.
  • oxaliplatin herein refers to the compound [(1R, 2R) -cyclohexane-1,2-diamine] ((2-)-O, O ') platinate.
  • the oxaliplatin is injected 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg / kg / time per injection, 1, 2, 3, 4, 5, 6, or 7 injections for 1 week, or continuous injections for 2, 3, 4, 5, or 6 weeks.
  • the oxaliplatin is injected 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 mg / m 2 / times, 1, 2 , 3, 4, 5, 6 or 7 times per week, 1 week injection, or continuous 2, 3 injections , 4, 5 or 6 weeks.
  • the term "5-fluoropyrimidine” herein refers to the compound 5-fluoro-1H-pyrimidine-2,4-dione.
  • the 5-fluorouracil or prodrug or active metabolite thereof is administered in an amount of 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 mg / kg / time, 1, 2, 3, 4, 5, 6, or 7 times per week, 1 week injection, or 2, 3, 4 continuous injections , 5 or 6 weeks; in certain embodiments, the 5-fluorouracil or prodrug or active metabolite thereof is administered in an amount of 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900 mg /
  • the prodrug of 5-fluorouracil is capecitabine.
  • the capecitabine or its prodrug or active metabolite is administered in an amount of 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660 , 665, 670, 675, 680, 685, 690, 695, 700 mg / m 2 / times, 1, 2, 3, 4, 5, 6, or 7 times per week, 1 week injection, or continuous injection of 2, 3 , 4, 5 or 6 weeks.
  • epirubicin refers to the compound 10-[(3-amino-2,3,6-trideoxy-A-L-alpha-hexylpyranosyl) oxy] -7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl) -methoxy- (8S-CIS) -tetrabenzo-5,12-dione.
  • antibody refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains or antigen-binding fragments thereof interconnected by disulfide bonds.
  • antibody also includes all recombinant forms of antibodies, particularly antibodies described herein, such as antibodies expressed in prokaryotic cells, unglycosylated antibodies, as well as antibody-binding antibody fragments and derivatives described below.
  • Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • VH and VL can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are scattered in more conserved regions called framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminal to the carboxy terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, which include various cells of the immune system (such as effector cells) and the first component of the classical complement system (C1q)
  • the term "monoclonal antibody” as used herein refers to a preparation of antibody molecules consisting of a single molecule. Monoclonal antibodies show single binding specificity and affinity for a particular epitope. In one embodiment, the monoclonal antibody is produced by a hybridoma that includes B cells derived from a non-human animal (e.g., mouse) fused with biochemical cells.
  • the antibody described herein may be a recombinant antibody, and the "recombinant antibody” includes all antibodies prepared, expressed, produced or isolated by recombinant means, such as (a) an animal (such as a mouse) from an immunoglobulin gene to a transgene or transchromosome ) Or an antibody isolated from a hybridoma prepared therefrom, (b) an antibody isolated from a host cell (eg, a transfected tumor) transformed to express the antibody, (c) an antibody isolated from a recombinant combinatorial antibody library, And (d) antibodies produced, expressed, produced or isolated by any other means involving splicing of immunoglobulin gene sequences into DNA sequences.
  • recombinant antibody includes all antibodies prepared, expressed, produced or isolated by recombinant means, such as (a) an animal (such as a mouse) from an immunoglobulin gene to a transgene or transchromosome ) Or an antibody isolated from a hybridoma prepared therefrom, (b) an
  • humanized antibody herein refers to a CDR sequence in which a germline derived from another mammalian species, such as a mouse, is grafted onto a human framework sequence. Additional framework region modifications can also be made in human framework sequences and CDR sequences derived from germlines of another mammalian species.
  • chimeric antibody herein refers to an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, for example, the variable region sequence is derived from a mouse antibody and the constant region sequence source is Antibodies from human antibodies.
  • Fab or "Fab region” herein includes polypeptides comprising VH, CH1, VL, and CL immunoglobulin domains. Fab may refer to this region isolated, or this region located in the context of a full-length antibody or antibody fragment.
  • Fc or "Fc region” herein includes a polypeptide comprising an antibody constant region other than the first constant region immunoglobulin domain. Thus, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, and the flexible hinge at the N-terminus of these domains. For IgA and IgM, the Fc may include a J chain.
  • the Fc includes the immunoglobulin domains C ⁇ 2 and C ⁇ 3 and the hinge between C ⁇ 1 and C ⁇ 2.
  • the human IgG heavy chain Fc region is generally defined as containing residues C226 or P230 at its carboxy terminus, where numbering is according to Kabat's EU index.
  • Fc is defined herein as including residue P232 to its carboxy terminus, where numbering is according to the EU index in Kabat.
  • Fc can refer to this region isolated, or to a region in an Fc polypeptide, such as an antibody, in the environment.
  • the term “hinge” or “hinge region” or “antibody hinge region” herein includes a flexible polypeptide comprising an amino acid between the first and second constant domains of an antibody. Structurally, the IgGCH1 domain starts at EU220 and the IgGCH2 domain starts at residue EU237.
  • the antibody hinge is defined herein as including positions 221 (D221 of IgG1) to 231 (A231 of IgG1), where numbering is according to Kabat's EU index.
  • variant includes antibody sequences that differ from the parent antibody sequence due to at least one amino acid modification compared to the parent antibody.
  • the variant antibody sequences herein preferably have at least about 80%, preferably at least about 90%, and more preferably at least about 95% amino acid sequence identity to the parent antibody sequence.
  • An antibody variant may refer to the antibody itself, a composition comprising the parent antibody, or an amino acid sequence encoding it.
  • amino acid modification herein includes amino acid substitutions, insertions and / or deletions in a polypeptide sequence.
  • amino acid substitution or “substitution” herein is meant the replacement of an amino acid at a particular position in the parent polypeptide sequence with another amino acid.
  • substitution of R94K means that the arginine at position 94 is replaced by a lysine, which is a variant of the heavy chain variable framework region.
  • 94K means that the 94 position is replaced with lysine.
  • multiple substitutions are usually separated by slashes.
  • R94K / L78V refers to a double variant comprising the substitutions R94K and L78V.
  • amino acid insertion or “insertion” means the addition of an amino acid at a particular position in the parent polypeptide sequence.
  • insert -94 indicates an insert at 94 bits.
  • amino acid deletion or “deletion” means the removal of an amino acid at a particular position in a parent polypeptide sequence.
  • R94- indicates deletion of arginine at position 94.
  • full-length antibody includes structures that make up the natural biological form of the antibody, including variable and constant regions.
  • the full-length IgG antibodies are tetramers, consisting of two identical pairs of immunoglobulin chains, each pair having a light chain and a heavy chain, Each light chain contains immunoglobulin domains VL and CL, and each heavy chain contains immunoglobulin domains VH, CH1 (C ⁇ 1), CH2 (C ⁇ 2), and CH3 (C ⁇ 3).
  • IgG antibodies may consist of only two heavy chains, each heavy chain comprising a variable domain linked to the Fc region.
  • Antibody fragments include, but are not limited to: (i) Fab fragments consisting of VL, VH, CL and CH1 domains, including Fab 'and Fab'-SH, (ii) Fd fragments consisting of VH and CH1 domains, (iii) Fv fragment consisting of VL and VH domains of a single antibody; (iv) dAb fragment consisting of a single variable region; (v) F (ab ') 2 fragment, a bivalent fragment containing 2 linked Fab fragments; (vi) single-chain Fv molecule antigen binding site; (vii) bispecific single-chain Fv dimer; (viii) "dibody” or “tribody”, a multivalent or multispecific fragment constructed by gene fusion And (ix) scFv genetically fused to the same or different antibodies.
  • Antibodies are classified into isotypes based on constant region gene assays.
  • Human constant light chains are divided into ⁇ (C ⁇ ) and ⁇ (C ⁇ ) light chains.
  • the heavy chain is divided into ⁇ , ⁇ , ⁇ , ⁇ , or ⁇ and defines the isotypes of antibodies, IgM, IgD, IgG, IgA, and IgE, respectively.
  • IgGs are commonly used for therapeutic purposes. In humans, this category includes the subclasses IgG1, IgG2, IgG3, and IgG4. In mice, this category includes the subclasses IgG1, IgG2a, IgG2b, and IgG3.
  • IgM has subclasses, including but not limited to IgM1 and IgM2.
  • IgA has several subclasses, including but not limited to IgA1 and IgA2.
  • isotype means any class or subclass of immunoglobulin defined by the chemical and antigenic characteristics of the constant region.
  • the known human immunoglobulin isotypes are IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM1, IgM2, IgD, and IgE.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • enhancing ADCC effector function may mean enhanced potency or enhanced efficacy.
  • Tier as used in the experimental context means the concentration (half-large effective concentration) of the antibody when observing a specific therapeutic efficacy EC50.
  • Effectiveacy as used in the experimental context means the large possible effector function of an antibody at a saturated level.
  • ADCP antibody-dependent cell-mediated phagocytosis
  • CDC complement-dependent cytotoxicity
  • complement protein components recognize antibodies bound on a target cell, which then results in the lysis of the target cell.
  • effector function includes a biochemical event caused by the interaction of an Fc region of an antibody with an Fc receptor or ligand. Effector functions include Fc ⁇ R-mediated effector functions, such as ADCC and ADCP, and complement-mediated effector functions, such as CDC.
  • body surface area (m2) 0.0061 ⁇ height (cm) + 0.0128 ⁇ weight (kg)-0.1529.
  • Solution: 0.0061 ⁇ 168 + 0.0128 ⁇ 55-0.1529 1.576m2
  • the heavy and light chain variable region sequences of the antibodies listed in the present invention can each bind human dense protein 18A2, and the heavy and light chain variable region sequences can be "mixed and matched" to produce the anti-human dense protein 18A2 of the present invention. Binding molecule.
  • the invention also provides variants of antibodies or fragments thereof that bind human avidin 18A2. Accordingly, the invention also includes antibodies or fragments thereof having a heavy or light chain variable region sequence that is at least 80% of the heavy and / or light chain variable region sequence of an antibody specifically disclosed herein Amino acid sequence identity.
  • the amino acid sequence identity is at least 85%, more preferably at least 90%, preferably at least 95%, especially 96%, more particularly 97%, even more particularly 98%, especially 99%, including for example 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99% and 100%.
  • sequence identity can be determined by standard methods commonly used to compare amino acid position similarities of two polypeptides.
  • a computer program such as BLAST or FASTA is used to align the two amino acids for a good match (along the full length of one or two sequences or along a predetermined portion of one or two sequences).
  • the program provides default open penalties and default gap penalties.
  • a scoring matrix such as PAM250 can be used in conjunction with a computer program. For example, percent identity can be calculated as: the total number of identical matches multiplied by 100, divided by the total length of the longer sequence in the match span and the number of empty spaces poured into the longer sequence in order to compare the two sequences.
  • framework sequences can be used to engineer variable regions to produce variant antibodies.
  • the variant antibodies of the present invention include variants in which framework region residues in VH and / or VK are modified, for example, to improve the characteristics of the antibody.
  • framework region modifications are made to reduce the immunogenicity of the antibody.
  • one approach is to "backmutate" one or more framework region residues to the corresponding murine sequence, or "backmutate” one or more framework region residues to the corresponding germline sequence.
  • the present invention provides a humanized antibody or fragment thereof that binds human avidin 18A2, wherein the framework region of at least one heavy chain variable region of the humanized antibody or fragment thereof comprises At least one amino acid modification of the corresponding framework region of the heavy chain variable region.
  • the amino acid modification is an amino acid substitution.
  • no more than five, preferably no more than four, more preferably no more than three, even more preferably no more than two, and preferably no more than one amino acid modification are performed in the framework region.
  • the invention also provides humanized antibodies and fragments thereof that bind human dense protein 18A2, which also include human heavy and / or light chain constant domains.
  • the human heavy chain constant region can be selected from the group of human immunoglobulins consisting of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM1, IgM2, IgD, and IgE, and human heavy chain constant region IgG, especially IgG1 is preferred.
  • the human light chain constant region may be selected from the group of human immunoglobulins composed of K or lambda constant regions, and human K constant regions are preferred.
  • the humanized antibody or fragment thereof comprises a human IgG1 heavy chain constant domain and a human light chain K constant domain.
  • the present invention also provides a humanized antibody or fragment thereof that binds human avidin 18A2, which includes a human heavy chain and / or light chain constant region, wherein the human heavy chain constant region includes CH1 of human IgG1, a hinge region of human IgG1, and Isotype variants of the Fc region of human IgG3.
  • a preferred humanized antibody comprising an isotype variant is a full-length antibody.
  • the sequence includes a heavy chain variable region sequence comprising SEQ ID NO: 12, 14, 15, 55, or 57 and a sequence comprising SEQ ID NO: 11, 13, 56, or 58. The sequence of the light chain variable region is shown.
  • a combination of the heavy chain variable region shown in SEQIDNO: 12 and the light chain variable region shown in SEQIDNO: 11 is preferred; or the sequence of the heavy chain variable region shown in SEQIDNO: 14 or 15 and the sequence shown in SEQIDNO: 13 are preferred.
  • Effector functions are usually complement-dependent cytotoxicity (CDC) and / or C1q binding and / or antibody-dependent cell-mediated cytotoxicity (ADCC) and / or antibody binding affinity to Fc ⁇ receptors, preferably complement-dependent cells Toxicity (CDC) and / or antibody-dependent cell-mediated cytotoxicity (ADCC).
  • CDC complement-dependent cells Toxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • the binding affinities of CDC, C1q binding, ADCC, and antibodies to the Fc ⁇ receptor are measured by standard in vitro assays known in the art and commercially available.
  • ADCC is measured by a lactate dehydrogenase (LDH) release assay
  • CDC is measured by an assay administered to a cell.
  • Standard assays to assess the binding capacity of antibodies such as human claudin 18A2 are known in the art and include, for example, ELISA, Western blot, and flow cytometry analysis. Suitable assays are described in detail in the examples.
  • 293T cells stably transfected with CLD18A2 AGS cells stably transfected with CLD18A2, NCI-N87 cells stably transfected with CLD18A2, BGC cells stably transfected with CLD18A2, and flow cytometric analysis Determine EC50.
  • the antibody targeting CLD18A2 selected in this example is a humanized antibody, which has a heavy chain variable region shown in SEQ ID NO: 15 and a light chain variable region shown in SEQ ID NO: 13 and a nucleoside of the light chain.
  • the acid sequence is shown in SEQ ID NO: 60
  • the heavy chain nucleotide sequence is shown in SEQ ID NO: 59.
  • Amplification of the light and heavy chain variable regions was performed according to the "step-out PCR" method described by Matz et al. (Nucleic Acids Research, 1999, Vol. 27, No. 6).
  • the nucleotides of the light chain (sequence shown in SEQ ID NO: 60) and the nucleotides of the heavy chain (sequence shown in SEQ ID NO: 59) were cloned to true by standard methods known to those skilled in the art.
  • Nuclear expression vector. 293F cells in the logarithmic growth phase were transiently transfected with 293fectin TM Transfection reagent (Invitrogen, 12347-019) or polyethyleneimine (PEI) (Sigma-Aldrich, 408727).
  • the above eukaryotic expression vector uses the vector pH or vector pK used by CN101602808B.
  • mice 2 ⁇ 2 ⁇ 2mm PDX tumors of gastric cancer were inoculated on BALB / c mice (D0 on the day of inoculation), and the tumors were inoculated subcutaneously for D27 days.
  • the average tumor volume was 128mm 3 , and the model of gastric cancer PDX-GA0006 was obtained.
  • the tumor-forming mice were randomly divided into 6 groups, namely the vehicle group, the antibody group (Ab group), the EOF group, the EOF + Ab group, the OF group, and the OF + Ab group, and the general clinical symptoms of the animals were observed during the experiment.
  • the body weight and tumor diameter were measured twice, and on day D51, mice were euthanized.
  • the method of administration is as follows:
  • Vehicle group intraperitoneal injection, 3 times a week.
  • Ab group CLD18A2 antibody prepared in Example 1, 40 mg / kg, intraperitoneal injection, 3 times a week.
  • EOF group epirubicin hydrochloride (1.25 mg / kg) for intraperitoneal injection + oxaliplatin (3.25 mg / kg) for injection + fluorouracil injection (56.25 mg / kg), once a week; vehicle, Intraperitoneal injection, 3 times a week.
  • EOF + Ab group EOF (epirubicin hydrochloride (1.25mg / kg) + oxaliplatin for injection (3.25mg / kg) + fluorouracil injection (56.25mg / kg)) given once a week, CLD18A2 antibody (40mg / kg) 3 times a week.
  • OF group oxaliplatin for injection (3.25mg / kg) + fluorouracil injection (56.25mg / kg), once a week; vehicle, intraperitoneal injection, three times a week.
  • OF + Ab group OF (Oxaliplatin for injection (3.25mg / kg) + Fluorouracil injection (56.25mg / kg)) was administered once a week, and CLD18A2 antibody (40mg / kg) was administered three times a week.
  • Tumors were obtained after euthanasia of mice, and tumor weights were weighed. The results are shown in Figs. 3 and 4.
  • the tumor load was too large.
  • One mouse died at 51 days after tumor inoculation.
  • the tumor suppression rates of the groups were: Ab group, 1.21%; EOF group, 48.70%; EOF + Ab group, 69.46%; OF group, 71.64%; OF + Ab group, 96.86%, and tumor regression of 1 mouse among 5 mice in this group (* p ⁇ 0.05; ** p ⁇ 0.01 or *** p ⁇ 0.001, Oneway ANOVA).
  • Example 2 Referring to the operation of Example 2, the tumor-forming mice were given different doses of the antibodies, and the specific administration methods were as follows:
  • AB1 the CLD18A2 antibody prepared in Example 1 was administered at a dose of 40 mg / kg, intraperitoneally, 3 times a week for 2 weeks.
  • the CLD18A2 antibody prepared in Example 1 was administered at a dose of 70 mg / kg, intraperitoneally, 3 times a week for a total of 2 weeks.
  • AB3 the CLD18A2 antibody prepared in Example 1 was administered at a dose of 100 mg / kg, intraperitoneally, 3 times a week for a total of 2 weeks.
  • the tumor growth results are shown in Figure 5, which shows that the administration of the AB3 group has a better anti-tumor effect.
  • the weight change of the mice is shown in Figure 6, and there is no significant change in body weight, indicating that the administration of a large dose of CLD18A2 antibody To better antitumor effect, and the side effects are small.
  • an example of an antibody using the humanized antibody CLD18A2 is used.
  • Those skilled in the art may use other antibodies according to the teaching of the present application, such as those containing SEQ ID NO: 12.
  • the light chain variable region antibody shown in SEQ ID NO: 58 is also used.

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Abstract

L'invention concerne une méthode de traitement de tumeurs CLDN18 positives, dans laquelle un anticorps qui reconnaît spécifiquement la protéine CLDN18 et des médicaments chimiothérapeutiques sont administrés à un sujet qui en a besoin. Les médicaments chimiothérapeutiques comprennent : le 5-fluorouracile, un promédicament de celui-ci, ou un métabolite actif de celui-ci, et l'oxaliplatine, un promédicament de celui-ci, ou un métabolite actif de celui-ci ; ou le 5-fluorouracile, un promédicament de celui-ci, ou un métabolite actif de celui-ci, l'oxaliplatine, un promédicament de celui-ci, ou un métabolite actif de celui-ci, et un médicament à base de taxane. L'invention concerne également une combinaison prête-à-l'emploi pour le traitement de tumeurs CLDN18 positives. Par comparaison avec la technologie existante, la méthode de traitement et la combinaison prête-à-l'emploi présentent un taux de suppression tumorale considérablement amélioré et de meilleurs effets anti-tumoraux. De plus, la présente invention peut réduire l'utilisation de médicaments chimiothérapeutiques et améliorer la sécurité des médicaments et leur tolérance par les patients.
PCT/CN2019/109214 2018-09-30 2019-09-29 Polythérapie combinant anticorps anti-cldn18 et médicaments chimiothérapeutiques WO2020063988A1 (fr)

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WO2022126687A1 (fr) * 2020-12-16 2022-06-23 广州百暨基因科技有限公司 Anticorps anti-claudine 18.2 ou fragment de liaison à l'antigène et utilisation associée
WO2022136642A1 (fr) 2020-12-23 2022-06-30 Sotio Biotech A.S. Conjugués anticorps-médicament anti-claudine 18.2 spécifiques d'une tumeur
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WO2022122709A1 (fr) 2020-12-07 2022-06-16 Sotio Biotech A.S. Conjugués anticorps-médicament à base d'anticorps cldn18.2 humanisés
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WO2022136642A1 (fr) 2020-12-23 2022-06-30 Sotio Biotech A.S. Conjugués anticorps-médicament anti-claudine 18.2 spécifiques d'une tumeur
WO2022206975A1 (fr) * 2021-04-02 2022-10-06 原启生物科技(上海)有限责任公司 Protéine de liaison à l'antigène cldn18.2 et son utilisation
WO2023078386A1 (fr) * 2021-11-05 2023-05-11 正大天晴药业集团股份有限公司 Anticorps anti-cldn18.2 et son utilisation

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KR20210072027A (ko) 2021-06-16
US20220033491A1 (en) 2022-02-03
CN112888458A (zh) 2021-06-01
EP3858384A1 (fr) 2021-08-04
JP2022511394A (ja) 2022-01-31

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